X xx-x x-x



Patented Aug. 26, 1952 'jflWUNITED;

OF PREPARING SAME Ian MorrisHeilbron and Basil CharlesLeicester Weedon,London, Ewart Ray Herbert Jones, Manchester, Benjamin Arthur Hems; Northolt,

vand Alexander Bertus Arnold-Jansen, London,

England, assignors to Glax'o Laboratories Limited, Greeni'ord, England,a. British company No Drawing. Application March'l, 1950, Serial No.13,265. In Great Britain March 22,1949

"I'hisinvention is concerned with improvements in or relating to thepreparation or a newunsaturated carbinol, namely 3:7-dimethyl-14:6:8-trien-1-yn-3- o1 which may be represented by-the followingstructural formula and whichis of use inthesynthesis of vitamin A. Wehave ioundthat the new carbinol can conveniently be prepared by reactinga halogeno ma nesium derivative of 2 t 6: 6:F-trimethyl-lethynylcyclohexene with 6 -methylocta-3 :5 :7- trien-z onein thepresence 01' an inert solvent as herein definedfand subsequentlydecomposing the resulting complexiormed; this reaction may berepresented as follows: I

CH: CH:

where X is chlorine or bromine. l

n Accordingly-the invention comprises the new compound,3 ;7 dihithylmeans trimethylf cyclohex-1"-enyl) nona j- 4:6: 8-trien-l1-yn-'3-olrepresented by thestructural formula j" jficcording-to a further'Ieature oi. the invention '10 Claims. (Cl. 260-617) we provide aprocess iorthe preparation oi 327- n a 2 nonaiz 6:S-trien-l-yn-B-ol inwhich a halogeno magnesium derivative of the general formula W V a B HwhereX has the above stated meaning is reacted with 6-methy1octa-3 :5:7-trien-2-one in the presence of an inert solvent as herein defined andthe resulting organo-magnesium complex decomposed to yield the desiredcarbinol.

' The term inert solvent as used herein means an organic solvent whichhas no demonstratable action on the reactants or the products 01' thereaction, other than the normal action of solvents in Grignardreactions. At present we prefer to use aliphatic ethers or cyclicaliphatic ethers having from 4-10 carbon atoms, for example diethylether, dibutyl ether, tetrahydroiuran or dioxane; other inert solventsmay if desired be used in conjunction with these sol- 'vents. It is alsopreferable that the solvent used should be as dry as possible.

The first stage of the process is preferably carried out at temperatureswithin the range of from -30 to +20 C., preferably in an inertatmosphere for example in an atmosphere of nitrogen. It is generallydesirable to have present a small quantity of an anti-oxidant such ashydroquinone. v 1

r The second stage of theprocess, namely the decomposition'of the organomagnesium complex may be carried out by conventional methods for exampleby the use or water which may contain other reagents. The use ofstrongly acidic reagents in the decomposition should preferably beavoided as such reagents may cause rearrangement of the carbinol. Atpresent we prefer to use an aqueous solution of ammonium chloride forthe decomposition which may be effected at low temperatures, for example0 C. The haloseno magnesium derivative oi! 216:6-trimethyl-l-ethynylcyclohexene may be prepared by conventional methods;we prefer, according to a further feature of the invention to preparethis E{ 1475, 1253 and 625. respectively. 6, 43700, 37400, and 185.00,-respectively;

271 and 281 mminfiea. mazes.

It will be understood that these characteristics."

were determined on the purest. material we. have been able to obtain andmay be subject to variation dependent on the purity of theproduct.

2 6 G-trimethyl-l-ethynylcyclohexene may be. prepared by any convenientmethod but at pres..- ent we prefer to use the method described in thecopending application of John Haroldv Chapman, Serial No. 143,342, filedFebruary 9, 1950, now Patent No. 2584591559. An alternative method ofpreparation is described in specification No. 627,453.

G-methyloeta-B':5:7trien-2 one may be prepared by any convenient methodbut at present we prefer to use the process described in the copendingapplication of Alexander Bertus Arnold Jansen, Serial No. 148,264, filedMarch 7, 1950. Another method of preparing this compound, is, describedin the, oopending application organ M, Heilbron, ct a1, Serial lNo.148,261, filed Marclifl, 1950.

In order that the invention may be well understood the following.examples are given. only as illustrations: 1 p 7 I E M L 1 2 6":6-trimethy 1= 1- ethynylcyclohex-l-ene ('3 g.) in'dry ether: ('15 c..)1was] added to a solution oi" ethyl magnesium bromide (from 0.6g.magnesium) in ether (20, 0.13.); The mixture. was refiuxed'undernitrogen for two hours and was then cooled infanilee'bath.6-methyl'octae3t5 :7+ trien-2-0I e 3' gJ' ineilther (I 0,. 0.); was thenaddedtlropwise with. stirring. Ajiter two hours sti r ng. at. 0 C. themixture. was. treated. with x es of. an. ammonium chloride solution. anthe. ethereallayer washed with water, dried andevap Qif ted-i frzheresidual brown, 011 (5.8. a"). a 1;.5600; showedlab rptionlmaximaamt-2'71 andZSfi 1058' and; fi9'7 respectivelyqand an infiexi'onat Y Wt-1 .3191:

. Found. on. a portion. distilled. at- 1305-. 1C;/ 1.0.? 84.2%.; H. 9.1% .(izolrlnfiliequires; Q; 8A;.5;% H 919. %-v -...11. .I

.EXALEPLE 2..

drofuran (7.0;ml.) wasadded slowly ati-I-ZOCJto (5.0 g.) in water (15ml.) was added to decompose the complex. The mixture was extracted with:ether; and the extracts washed with water and; dri d over ah ymusfimasnesium. sulp Evaporation of the solvent under vacuum gave3-:7-dimethy1-1-(2' 6' 6'- trimethylcyclohex 1-en-1-yl),nona-4:fiz8-trien-l-yn-3-ol (2.9 g.) as a; viseouspoil 11115800.

U. V. absorption;

U ing di-n-butyl ether as solvent Using dioman ds solvent The G-rigna-rdderivative of 1-ethynyl-2: 6:6- trimethylcyclohexene was preparedexactly as in Example 2, except that the solvent used was diether. 6,methy.locta 3 5 7-.trien-2-one, (2.0 g.) in di'oxandt'l ml.) was thenadded; slowly at room'temperatur'e and the, mixture stirred, for. afurther 2 hours. Decomposition, of the 'cd' p fx w t ammo i before igave. methylgcy'cloheifv 1 :6, v I=yn=3 ol (1.5 an) "as; viscous" oir 115 1155315 1 i U. V. absorption:

Inflex. 274-283 mg 1% Max. 271 m Max. 229 mu 1. As a new compound,3:7-dimethy1a(2. ":6":- 6 trimethylcyclohex-1,'-enyl) -nona 41628-t'rien-11-yn-3-ol represented by the structural formu a tit"marital-a fatcomprises sreacting rivative oi the general where 2 ma Wbs? eestwa ensstmaor l rm ed th r1 -e m- :0 1:-

'P sence-ntzm inentsqxtzenla solvent and at a temperature within therange of --30 to +20 C. and decomposing the resulting organo magnesiumcomplex to yield said carbinol.

3. A process as claimed in claim 2 in which the inert solvent is anether selected from the group consisting of aliphatic and cyclicaliphatic ethers having from 4 to carbon atoms.

4. A process as claimed in claim 2 in which the first stage of theprocess is carried out at a temperature within the range of -30 to +20C. in an inert atmosphere, and in the presence of an anti-oxidant.

5. A process as claimed in claim 2 in which the organo magnesium complexis decomposed with an aqueous solution of ammonium chloride at a lowtemperature of the order of 0 C.

6. The process as claimed in claim 2, in which said solvent is di-ethylether.

7. The process as claimed in claim 2, in which said solvent isdi-n-butyl ether.

8. The process as claimed in claim 2, in which said solvent istetrahydrofuran.

9. The process as claimed in claim 2, in which said solvent is dioxane.

10. A process for the preparation of the carbinol 3 7 -dimethyl- (2 :6:6 -trimethylcyclohexl'-enyl) -nona-4 6 8-trien-1-yn-3-ol whichcomprises reacting ethyl magnesium bromide with 2:6:6-trimethyl-1ethynylcyclohexene in the presence of an inert solvent, reacting theproduct of said reaction with 6-methylocta-325:7-trien- 2-one in thesame solvent and at a temperature within the range of to +20 C. anddecomposing the resulting complex to yield said carbinol. I

IAN MORRIS HEILBRON.

BASIL CHARLES LEICESTER WEEDON.

EWART RAY HERBERT JONES.

BENJAMIN ARTHUR HEMS.

ALEXANDER BERTUS ARNOLD JANSEN.

REFERENCES CITED The following references are of record in the file ofthis patent:

Gilman, Organic Chemistry, an Advanced Treatise (1943), p. 496, J. Wileyand Sons, New York.

Tome, Thesis for BS degree at Mass. Inst. of Tech., May 23, 1947, pp. 6,14 and 15.

Milas, The Synthesis of Vitamin A (1947), p. 24 (a reprint from Vitaminsand Hormones, v01. V, 1947), (New York).

Cheeseman, Heilbron, Jones, Sondheimer and Weedon, Journal of theChemical Society, 2031- 35, August 1949 (London).

1. AS A NEW COMPOUND,3::7-DIMETHYL-(2'':6'':6''-1-TRIMETHYLCYCLOHEX-1''-ENYL)-NONA-4:6:8-TRIEN-1-YN-3-OLREPRESENTED BY THE STRUCTURAL FORMULA